Pyrazolopyrimidine pde 10 inhibitors

ABSTRACT

The present invention is directed to pyrazolopyrimidine compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington&#39;s disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

FIELD OF THE INVENTION

The invention relates generally to compounds which act as inhibitors of the phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Schizophrenia is a debilitating disorder affecting the psychic and motor functions of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been less than acceptable and result in an extremely high rate of noncompliance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects. The side effects have been associated with significant metabolic, extrapyramidal, prolactic and cardiac adverse events. See Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.

While multiple pathways are believed to be involved with the pathogenesis of schizophrenia leading to psychosis and cognition deficits, much attention has focused on the role of glutamate/NMDA dysfunction associated with cyclic guanosine monophosphate (cGMP) levels and the dopaminergic D2 receptor associated with cyclic adenosine monophosphate (cAMP). These ubiquitous second messengers are responsible for altering the function of many intracellular proteins. Cyclic AMP is thought to regulate the activity of cAMP-dependent protein kinase (PKA), which in turns phosphorylates and regulates many types of proteins including ion channels, enzymes and transcription factors. Similarly, cGMP is also responsible for downstream regulation of kinases and ion channels.

One pathway for affecting the levels of cyclic nucleotides, such as cAMP and cGMP, is to alter or regulate the enzymes that degrade these enzymes, known as 3′,5′-cyclic nucleotide specific phosphodiesterases (PDEs). The PDE superfamily includes twenty one genes that encode for eleven families of PDEs. These families are further subdivided based on catalytic domain homology and substrate specificity and include the 1) cAMP specific, PDE4A-D, 7A and 7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C, and 9A, and 3) those that are dual substrate, PDE 1A-C, 2A, 3A and 3B, 10A, and 11A. The homology between the families, ranging from 20% to 45% suggests that it may be possible to develop selective inhibitors for each of these subtypes.

The identification of PDE10 was reported by three groups independently and was distinguished from other PDEs on the basis of its amino acid sequence, functional properties, and tissue distribution (Fujishige et al., J. Biol. Chem. (1999) 274:18438-18445; Loughney et al., Gene (1999) 234: 109-117; Soderling et al., PNAS, USA (1999) 96: 7071-7076). The PDE10 subtype at present consists of a sole member, PDE10A, having alternative splice variants at both the N-terminus (three variants) and C-terminus (two variants), but that does not affect the GAF domain in the N-terminus or the catalytic site in C-terminus. The N-terminus splice variants, PDE10A 1 and PDE10A2, differ in that the A2 variant has a PKA phosphorylation site that upon activation, i.e. PKA phosphorylation in response to elevated cAMP levels, results in intracellular changes to the localization of the enzyme. PDE10A is unique relative to other PDE families also having the conserved GAF domain in that its ligand is cAMP, while for the other GAF-domain PDEs the ligand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007) 17(2): 147-158). PDE10A has limited but high expression in the brain and testes. The high expression in the brain and, in particular, the neurons of the striatum, unique to PDE10, suggests that inhibitors thereto may be well suited from treating neurological and psychiatric disorders and conditions.

Inhibition of PDE10 is believed to be useful in the treatment of schizophrenia and a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and/or cGMP within neurons, including a variety neurological, psychotic, anxiety and/or movement disorders. Accordingly, agents that inhibit PDE10 and especially PDE10A would be desirable as therapeutics for neurological and psychiatric disorders.

SUMMARY OF THE INVENTION

The present invention is directed to pyrazolopyrimidine compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

X is —NR⁴R⁵ or —O—R⁵;

Y is —O—, —(CR³R⁴)—, —(C═O)NR⁴—, or a bond between the carbon of the pyrazolopyrimidine ring and R¹; R¹ is C₁₋₆alkyl, C₁₋₆alkyl-C₃₋₆cycloalkyl-, or —CH₂CH₂—C═C— which is unsubstituted or substituted with a substituent selected from the group consisting of:

-   -   (1) C₁₋₆alkyl, which is =substituted or substituted with         halogen, hydroxyl, or C₃₋₆cycloalkyl,     -   (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl, or C₃₋₆cycloalkyl,     -   (3) phenyl, which is unsubstituted or substituted with one to         five substituents selected from R⁶, R⁷ and R⁸,     -   (4) heteroaryl, which is unsubstituted or substituted with one         to five substituents selected from R⁶, R⁷ and R⁸,     -   (5) —O-phenyl, which is unsubstituted or substituted with one to         five substituents selected from R⁶, R⁷ and R⁸, and     -   (6) —O-heteroaryl, which is unsubstituted or substituted with         one to five substituents selected from R⁶, R⁷ and R⁸;         R² is selected from the group consisting of     -   (1) hydrogen,     -   (2) fluoro,     -   (3) C₁₋₆alkyl, and     -   (4) C₃₋₆cycloalkyl;         R³ is selected from the group consisting of:     -   (1) hydrogen, and     -   (2) C₁₋₆alkyl;         R⁴ is selected from the group consisting of     -   (1) hydrogen, and     -   (2) C₁₋₆alkyl;         R⁵ is C₁₋₆alkyl, C₁₋₆alkyl-C₃₋₆cycloalkyl or C₂₋₆alkenyl which         is unsubstituted or substituted with a substituent selected from         the group consisting of:     -   (1) halogen,     -   (2) hydroxyl,     -   (3) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (4) phenyl, which is unsubstituted or substituted with one to         five substituents selected from R⁶, R⁷ and R⁸, and     -   (5) heteroaryl, which is unsubstituted or substituted with one         to five substituents selected from R⁶, R⁷ and R⁸;         R⁶, R⁷ and R⁸ are independently selected from the group         consisting of:     -   (1) halogen,     -   (2) hydroxyl,     -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with         fluoro,     -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         fluoro,     -   (5) C₃₋₆cycloalkyl,     -   (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected         from the group consisting of hydrogen and C₁₋₆alkyl,     -   (7) —(C═O)—NR¹⁰R¹¹,     -   (8) —S(O)₂—NR¹⁰R¹¹,     -   (9) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is         selected from the group consisting of hydrogen and C₁₋₆alkyl,         and     -   (10) —CN;         R¹³ is selected from the group consisting of     -   (1) hydrogen, and     -   (2) C₁₋₆alkyl;         R¹⁴ is selected from the group consisting of:     -   (1) hydrogen, and     -   (2) C₁₋₆alkyl;         or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia:

wherein R¹ and R⁵ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib:

wherein R¹, R⁶ and R⁷ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic:

wherein R¹ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Id:

wherein R¹, R⁶ and R⁷ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein Y is —O—.

An embodiment of the present invention includes compounds wherein R¹ is —CH₂CH₂CH₂— or —CH₂-cyclopropyl-, which is substituted with a substituent selected from the group consisting of:

-   -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (3) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl),         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (4) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (5) —O-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro, and     -   (6) —O-heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro.

An embodiment of the present invention includes compounds wherein R¹ is —CH₂-cyclopropyl-, which is substituted in an (S,S) stereochemical orientation with a substituent selected from the group consisting of:

-   -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (3) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl),         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (4) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro,     -   (5) —O-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro, and     -   (6) —O-heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro.

An embodiment of the present invention includes compounds wherein R¹ is —CH₂-cyclopropyl-, which is substituted in a trans stereochemical orientation with a substituent selected from the group consisting of:

-   -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or hydroxyl,     -   (3) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl),         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (4) heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl),         —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted         with fluoro,     -   (5) —O-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro, and     -   (6) —O-heteroaryl, which is unsubstituted or substituted with         halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or         —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is         unsubstituted or substituted with fluoro.

An embodiment of the present invention includes compounds wherein R¹ is selected from the group consisting of:

An embodiment of the present invention includes compounds wherein R² is hydrogen.

An embodiment of the present invention includes compounds wherein R⁴ is hydrogen.

An embodiment of the present invention includes compounds wherein R⁵ is selected from the group consisting of:

An embodiment of the present invention includes compounds wherein R⁵ is selected from the group consisting of:

An embodiment of the present invention includes compounds wherein R⁵ is:

An embodiment of the present invention includes compounds wherein R⁵ is:

An embodiment of the present invention includes compounds wherein R⁵ is:

An embodiment of the present invention includes compounds wherein R¹³ is hydrogen and R¹⁴ is hydrogen.

Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

As appreciated by those of skill in the art, halogen or halo as used herein are intended to include fluorine, chlorine, bromine and iodine. Similarly, “alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. C₁₋₆, as in C₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. “Alkylene” means a straight or branched chain of carbon atoms with a group substituted at both ends, such as —CH₂CH₂— and —CH₂CH₂CH₂—. “Alkenyl” means a carbon chain which contains at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof such that C₂alkenyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons which incorporates at least one double bond, which may be in a E- or a Z-arrangement, including vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. “Alkynyl” means a carbon chain which contains at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof, such as ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. “Cycloalkyl” means a mono-, bi- or tri-cyclic structure, optionally combined with linear or branched structures, having the indicated number of carbon atoms, such as cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl, and the like. “Alkoxy” means an alkoxy group of a straight or branched chain having the indicated number of carbon atoms. C₁₋₆alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like. The term “heterocyclyl” as used herein includes both unsaturated heterocyclic moieties comprising a mono- or bicyclic aromatic rings with at least one ring containing a heteroatom selected from N, O and S, and each ring containing 5 or 6 atoms (i.e. “heteroaryl”) and saturated heterocyclic moieties comprising mono- or bicyclic saturated rings with at least one ring containing a heteroatom selected from N, O and S, and each ring containing 3, 5 or 6 atoms. Examples of “heteroaryl” include benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, furo(2,3-b)pyridyl, imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof. Examples of saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

A group which is designated as being substituted with substituents may be substituted with multiple numbers of such substituents. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents. The term “substituted” means that one or more hydrogens on the designated group is (are) replaced with a selection from the indicated group, provided that the designated group's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A reference to a “stable compound’ or “stable structure” means that the compound is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and to survive formulation into an efficacious therapeutic agent.

The compounds of the present invention may contain one or more stereogenic centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. The enantiomer of F-2 utilized for the synthesis of the more potent antipode of the claimed Examples was analyzed by vibrational circular dichroism (VCD) spectroscopy, and indicated that the absolute stereochemical designation at the 1- and 2-positions of the cyclopropyl ring is (S,S). The absolute stereochemical designation for all of the other compounds in the Examples was assigned based on this structural determination.

The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ²H and ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as 32P, sulfur such as ³⁵S, fluorine such as ¹⁸F, iodine such as ²³I and ¹²⁵I, and chlorine such as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

It will be understood that, as used herein, references to the compounds of present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cuprous, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like salts. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular embodiments citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention are the specific compounds disclosed in the Examples and herein. The subject compounds are useful in a method of treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. The subject compounds are useful in a method of inhibiting PDE10 activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The subject compounds are also useful for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.

The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof for use in medicine. The present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a mammalian patient in need thereof. The present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof.

“Treating” or “treatment of” a disease state includes: 1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; 3) or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

The subject treated in the present methods is generally a mammal, in particular, a human being, male or female, in whom therapy is desired. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with such disorders with an effective amount of the compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy to retard the progression or reduce the risk of the noted conditions, particularly in a patient who is predisposed to such disease or disorder.

Applicants propose that inhibitors of PDE10 and, in particular inhibitors of PDE10A, will provide therapeutic benefit to those individuals suffering from psychiatric and cognitive disorders. The unique and exclusive distribution of PDE10A in the medium spiny projection neurons of the striatum, which form the principle site for cortical and dopaminergic input within basal ganglia, suggests that it may be possible and desirable to identify inhibitors of PDE10 to ameliorate or eliminate unwanted cellular signaling within this site. Without wishing to be bound by any theory, Applicants believe that inhibition of PDE10A in the striatum will result in increased cAMP/cGMP signaling and striatal output, which has the potential to restore behavioral inhibition that is impaired in cognitive disease such as schizophrenia. Regulation and integration of glutamatergic and dopaminergic inputs will enhance cognitive behavior, while suppressing or reducing unwanted behavior. Thus, in one embodiment, compounds of the invention provide a method for treating or ameliorating diseases or conditions in which striatal hypofunction is a prominent feature or ones in which basal ganglia dysfunction plays a role, such as, Parkinson's disease, Huntington's disease, schizophrenia, obsessive-compulsive disorders, addiction and psychosis. Other conditions for which the inhibitors described herein may have a desirable and useful effect include those requiring a reduction in activity and reduced response to psychomotor stimulants or where it would be desirable to reduce conditional avoidance responses, which is often predictive of clinical antipsychotic activity.

As used herein, the term “‘selective PDE10 inhibitor” refers to an organic molecule that effectively inhibits an enzyme from the PDE10 family to a greater extent than enzymes from the PDE 1-9 or PDE11 families. In one embodiment, a selective PDE10 inhibitor is an organic molecule having a Ki for inhibition of PDE10 that is less than or about one-tenth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme. Preferably, a selective PDE 10 inhibitor is an organic molecule, having a Ki for inhibition of PDE10 that is less than or about one-hundredth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDE10 activity to the same degree at a concentration of about one-hundredth or less than the concentration required for any other PDE enzyme. A “selective PDE10 inhibitor” can be identified, for example, by comparing the ability of an organic molecule to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other PDE families. For example, an organic molecule may be assayed for its ability to inhibit PDE10 activity, as well as PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDE11A.

Phosphodiesterase enzymes including PDE10 have been implicated in a wide range of biological functions. This has suggested a potential role for these enzymes in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating a variety of neurological and psychiatric disorders.

In a specific embodiment, compounds of the present invention provide a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington D.C.) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizoid type, illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses.

In another specific embodiment, the compounds of the present invention provide a method for treating cognitive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term “cognitive disorders” includes the diagnosis and classification of these disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and/or cognition, such as dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal dementia, delirium, amnestic disorders or age related cognitive decline.

In another specific embodiment, compounds of the present invention provide a method for treating anxiety disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive-compulsive disorder and panic attack. As used herein, the term “anxiety disorders” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.

In another specific embodiment, compounds of the present invention provide a method for treating substance-related disorders and addictive behaviors comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term “substance-related disorders and addictive behaviors” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, substance-related disorders and addictive behaviors, such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.

In another specific embodiment, compounds of the present invention provide a method for treating obesity or eating disorders associated with excessive food intake, and complications associated therewith, comprising administering to a patient in need thereof an effective amount of a compound of the present invention. At present, obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization) as a general medical condition. The DSM-IV-TR also provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term “obesity or eating disorders associated with excessive food intake” includes the diagnosis and classification of these medical conditions and disorders described in ICD-10 and DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, obesity, bulimia nervosa and compulsive eating disorders.

In another specific embodiment, compounds of the present invention provide a method for treating mood and depressive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. As used herein, the term “mood and depressive disorders” includes the diagnosis and classification of these medical conditions and disorders described in the DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders.

In another specific embodiment, compounds of the present invention provide a method for treating pain comprising administering to a patient in need thereof an effective amount of a compound of the present invention. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.

In other specific embodiments, compounds of the invention provide methods for treating other types of cognitive, learning and mental related disorders including, but not limited to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive developmental disorder including autistic disorder, attention disorders such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor-related disorder, such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; a neurodegenerative disorder or condition, such as neurodegeneration associated with cerebral trauma, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-rigid syndromes (including, Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Huntington's disease, dyskinesia associated with dopamine agonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias, including tremor (such as, rest tremor, postural tremor, intention tremor and essential tremor), restless leg syndrome, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including, generalised myoclonus and focal myoclonus), tics (including, simple tics, complex tics and symptomatic tics), dystonia (including, generalised, iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such as blepharospasm, oromandibular, spasmodic, spasmodic torticollis, axial dystonia, hemiplegic and dystonic writer's cramp)); urinary incontinence; neuronal damage (including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema); emesis; and sleep disorders, including insomnia and narcolepsy. Of the disorders above, the treatment of schizophrenia, bipolar disorder, depression, including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorders, including autistic disorder, attention disorders including Attention-Deficit/Hyperactivity Disorder, autism, tlc disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.

The activity of the compounds in accordance with the present invention as PDE10 inhibitors may be readily determined without undue experimentation using a fluorescence polarization (FP) methodology that is well known in the art (Huang, W., et al., 3. Biomol Screen, 2002, 7: 215). In particular, the compounds of the following examples had activity in reference assays by exhibiting the ability to inhibit the hydrolysis of the phosphosphate ester bond of a cyclic nucleotide. Any compound exhibiting a Ki (inhibitory constant) below 1 μM would be considered a PDE10 inhibitor as defined herein.

In a typical experiment the PDE10 inhibitory activity of the compounds of the present invention was determined in accordance with the following experimental method. PDE10A2 was amplified from human fetal brain cDNA (Clontech, Mountain View, Calif.) using a forward primer corresponding to nucleotides 56-77 of human PDE10A2 (Accession No. AF127480, Genbank Identifier 4894716), containing a Kozak consensus sequence, and a reverse primer corresponding to nucleotides 2406-2413 of human PDE10A2 (Accession No. AF127480, Genbank Identifier 4894716). Amplification with Easy-A polymerase (Stratagene, La Jolla, Calif.) was 95° C. for 2 minutes followed by thirty three cycles of 95° C. for 40 seconds, 55° C. for 30 seconds, and 72° C. for 2 minutes 48 seconds. Final extension was 72° C. for 7 minutes. The PCR product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad, Calif.) according to standard protocol. AD293 cells with 70-80% confluency were transiently transfected with human PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturer specifications (Invitrogen, Carlsbad, Calif.). Cells were harvested 48 hours post-transfection and lysed by sonication (setting 3, 10×5 sec pulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and protease inhibitor cocktail (Roche). Lysate was collected by centrifugation at 75,000×g for 20 minutes. Supernatant containing the cytoplasmic fraction was used for evaluation of PDE10A2 activity. The fluorescence polarization assay for cyclic nucleotide phosphodiesterases was performed using an IMAP® FP kit supplied by Molecular Devices, Sunnyvale, Calif. (product # R8139). IMAP® technology has been applied previously to phosphodiesterase assays (Huang, W., et al., J. Biomol Screen, 2002, 7: 215). Assays were performed at room temperature in 384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 8 μL of each of 10 solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition is determined using a known PDE10 inhibitor, which can be any compound that is present at 5,000 times its Ki value in the assay described as follows, such as papaverine (see Siuciak, et al. Neuropharmacology (2006) 51:386-396; Becker, et al. Behav Brain Res (2008) 186(2):155-60; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795), 2-{-4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenoxymethyl}quinoline succinic acid or 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]quinoline succinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008) 325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3): 785-795). 0% of inhibition is determined by using DMSO (1% final concentrations).

A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is used to dispense 200 mL from each well of the titration plate to the 384 well assay plate. A solution of enzyme ( 1/1600 dilution from aliquots; sufficient to produce 20% substrate conversion) and a separate solution of FAM-labeled cAMP PDE from Molecular Devices (product # R7506), at a final concentration of 50 nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). The enzyme and the substrate are then added to the assay plates in two consecutive additions of 10 μL, and then shaken to mix. The reaction is allowed to proceed at room temperature for 30 minutes. A binding solution is then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction is stopped by addition of 60 μL of the binding solution to each well of the assay plates and the plates are sealed and shaken for 10 seconds. The plate was incubated at room temperature for at least one hour prior to determining the fluorescence polarization (FP). The parallel and perpendicular fluorescence of each well of the plate was measured using a Perkin Elmer EnVision™ plate reader (Waltham, Mass.).

Fluorescence polarization (mP) was calculated from the parallel (5) and perpendicular (P) fluorescence of each sample well and the analogous values for the median control well, containing only substrate (So and Po), using the following equation: Polarization (mP)=1000*(S/So−P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fitting the mP data to a four-parameter equation given below. The apparent inhibition constant (K_(I)), the maximum inhibition at the low plateau relative to “100% Inhibition Control” (Imax; e.g. 1=>same as this control), the minimum inhibition at the high plateau relative to the “0% Inhibition Control” (Imin, e.g. 0=>same as the no drug control) and the Hill slope (nH) are determined by a non-linear least squares fitting of the mP values as a function of dose of the compound using an in-house software based on the procedures described by Masser et al., JALA, 2003, 8: 54-63, using the following equation:

${mP} = {\frac{\left( {{0\% \mspace{14mu} {mP}} - {100\% \mspace{14mu} {mP}}} \right)\left( {{I\; \max} - {I\; \min}} \right)}{1 + \left\lbrack \frac{\lbrack{Drug}\rbrack}{\left( {10^{- {pK}_{1}}\left( {1 + \frac{\lbrack{Substrate}\rbrack}{K_{M}}} \right)} \right.} \right\rbrack^{nH}} + {100\% \mspace{14mu} {mP}} + {\left( {{0\% \mspace{14mu} {mP}} - {100\% \mspace{14mu} {mP}}} \right)\left( {1 - {I\; \max}} \right)}}$

The median signal of the “0% inhibition controls” (0% mP) and the median signal of the “100% inhibition controls” (100% mP) are constants determined from the controls located in columns 1-2 and 23-24 of each assay plate. An apparent (K_(m)) for PAM-labeled cAMP of 150 nM was determined in separate experiments through simultaneous variation of substrate and selected drug concentrations.

Selectivity for PDE10, as compared to other PDE families, was assessed using the IMAP® technology. Rhesus PDE2A3 and Human PDE10A2 enzyme was prepared from cytosolic fractions of transiently transfected HEK cells. All other PDE's were GST Tag human enzyme expressed in insect cells and were obtained from BPS Bioscience (San Diego, Calif.): PDE1A (Cat#60010), PDE3A (Cat#60030), PDE4AIA (Cat#60040), PDE5A1 (Cat#60050), PDE6C (Cat#60060), PDE7A (Cat#60070), PDE8A1 (Cat#60080), PDE9A2 (Cat#60090), PDE11A4 (Cat#60110).

Assays for PDE 1 through 11 were performed in parallel at room temperature in 384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 30 μL of each of ten solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition was determined by adding buffer in place of the enzyme and 0% inhibition is determined by using DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte, Sunnyvale, Calif.) was used to dispense 200 mL from each well of the titration plate to make eleven copies of the assay plate for each titration, one copy for each PDE enzyme. A solution of each enzyme (dilution from aliquots, sufficient to produce 20% substrate conversion) and a separate solution of PAM-labeled cAMP or PAM-labeled eGMP from Molecular Devices (Sunnyvale, Calif., product # R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP. The enzyme and the substrate were then added to the assay plates in two consecutive additions of 10 μL and then shaken to mix. The reaction was allowed to proceed at room temperature for 60 minutes. A binding solution was then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction was stopped by addition of 60 μL of the binding solution to each well of the assay plate. The plates were sealed and shaken for 10 seconds. The plates were incubated at room temperature for one hour, then the parallel and perpendicular fluorescence was measured using a Tecan Genios Pro plate reader (Tecan, Switzerland). The apparent inhibition constants for the compounds against all 11 PDErs was determined from the parallel and perpendicular fluorescent readings as described for PDE10 FP assay using the following apparent K_(M) values for each enzyme and substrate combination: PDE1A (FAM cGMP) 70 nM, rhesus PD2A3 (FAM cAMP) 10,000 nM, PDE3A (PAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1 (FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM, PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (FAM cGMP) 60 nM, PDE10A2 (FAM cAMP) 150 nM, PDE11A4 (FAM CAMP) 1000 nM. The intrinsic PDE10 inhibitory activity of a compound which may be used in accordance with the present invention may be determined by these assays.

The compounds of the following examples had activity in inhibiting the human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about 1 μM. Many of compounds within the present invention had activity in inhibiting the human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about 0.1 μM. Additional data is provided in the following Examples. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the PDE10 enzyme. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively inhibit PDE10 activity if it has a Ki of less than or about 1 μM, preferably less than or about 0.1 μM. The present invention also includes compounds within the generic scope of the invention which possess activity as inhibitors of other phosphodiesterase enzymes.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention may be desirable. However, the combination therapy may also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. Accordingly, the phatinaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. The subject compound and the other agent may be co-administered, either in concomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, atypical antipsychotics, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, Ata adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexyl, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The term “composition” as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions, oily suspensions, dispersible powders or granules, oil-in-water emulsions, and sterile injectable aqueous or oleagenous suspension may be prepared by standard methods known in the art. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.001 to 10 mg/kg. of body weight daily are administered to the patient, e.g., humans and elderly humans. The dosage range will generally be about 0.5 mg to 1.0 g. per patient per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions hereinabove. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; 13n: benzyl; Ac: acetyl; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl; DIPEA: N,N-diisopropylethylamine; DPPA: diphenylphosphorylazide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; EtOAc: ethyl acetate; HOBt: hydroxybenzotriazole hydrate; TEA: triethylamine; DMF: N,N-dimethylformamide; rt: room temperature; HPLC: high performance liquid chromatography; NMR: nuclear magnetic resonance; TLC: thin-layer chromatography.

X-ray powder diffraction was used to characterize solid samples for crystallinity and polymorphism. The X-ray powder diffraction data were acquired using a Rigaku MiniFlex II system and analyzed with the PDXL software. Thermal analysis was performed using a TA Instruments DSC Q2000. Samples of approximately 1-2 mg were weighed into a sample pan and a lid was loosely applied. The sample pan and empty reference pan were placed in the calorimeter; heating for standard experiments proceeded at 10° C./min. to approximately 300° C. Endotherms were integrated using Universal Analysis software. The endotherm onset and peak temperature are reported; enthalpy is not reported due to simultaneous decomposition with the melt event. Modulated DSC was employed for the characterization of amorphous solids, using a TA Instruments DSC Q2000. A modulation amplitude of ±0.5° C. and 60 second modulation period was applied to an underlying heating rate of 2° C./min to 200° C. Each sample was heated/cooled in 3 cycles to drive off the initial moisture content. The data from the second cycle were analyzed using Universal Analysis software, and the glass transition was determined as the inflection point between baselines in the reversing heat flow.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

A number of routes can be employed toward the synthesis of hydroxymethyl cyclopropanes of the form A5 (wherein R^(1a) is the substituent on R¹). In the most versatile route, a haloarene (A1) (wherein LG=halo) can undergo a facile Stille cross coupling with tributyl vinyl tin under standard conditions to afford vinylarenes A2. The terminal vinyl group is subsequently cyclopropanated with ethyl diazoacetate to afford a readily separable mixture of trans and cis cyclopropanes A3, with the trans diastereomer typically predominating. At this point, the enantiomers of the trans cyclopropane can be resolved by preparative chiral chromatography. Alternatively, the ester functionality can be reduced under standard conditions to afford alcohol A4, which can subsequently be resolved by preparative chiral chromatography.

In an alternative route to alcohols A5, haloarenes (A1) (wherein LG=halo) can undergo Suzuki cross coupling with vinyl boronate ester B1 to afford E-acrylate B2. Treatment of B2 with trimethyl sulfoxonium iodide and NaH affords the desired trans cyclopropane A3 in moderate to good yields. Following the protocol outlined in Reaction Scheme A, the racemic ester can be converted to enantiopure alcohol A5.

In yet another route to alcohols A5, aryl aldehydes (C1) can undergo a Horner-Wadsworth-Emmons olefination with triethyl phosphonoacetate under standard conditions to afford E-acrylate B2. Following the protocols outlined in Reaction Schemes B and A, the acrylate can be converted to enantiopure alcohol A5.

Functionalized alkoxy pyrzaolopyrimidines of the form D7 are prepared in a four-step sequence beginning with the condensation of dialkyl malonates with 3-aminopyrazoles to afford the corresponding dihydroxy core D3. Bis-chlorination with POCl₃ furnishes the dichloro core D4, which then undergoes a facile SNAr with a variety of primary and secondary amines under standard conditions. The reaction is completely selective for the 7-position over the 5-position. However, the resulting mono-chloro intermediate D5 is poorly reactive toward nucleophilic attack. To circumvent this reactivity issue, an efficient C—O cross coupling was developed. To this end, D7 can be prepared by the cross coupling of D5 with a variety of alcohols in the presence of TOSIPHOS ligand D6, Pd₂(dba)₃, and Cs₂CO₃.

Functionalized pyrzaolopyrimidines of the form E7 are prepared in a five-step sequence beginning with chiral alcohols E1. Halomethyl compounds E2 are prepared by treatment of E1 with the corresponding thionyl halide. Next, the halide is reacted with the dianion of a suitably functionalized ketoester (E3) to afford elaborated ketoester (E4). Condensation of E4 with 3-aminopyrazoles furnished the monohydroxy pyrazolopyrimidine core E5, which undergoes chlorination and a facile SNAr in a manner similar to that described in Reaction Scheme D to furnish compounds E7.

Example 1

(S,S)-Ethyl 2-(pyridin-2-yl)cyclopropanecarboxylate((S,S)-F1-trans)

A solution of 2-vinylpyridine (2 g, 19.02 mmol) in toluene (40 mL) was treated with ethyl diazoacetate (1.973 ml, 19.02 mmol) and stirred at reflux overnight. The mixture was concentrated in vacuo and the residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to elute peak 1; the solvent gradient was then ramped to 100% EtOAc to elute peak 2. This yielded the title compound (1.6 g, 44%) as the first eluting diastereomer, and the corresponding cis diastereomer (914 mg, 25%) as the second eluting diastereomer, both as yellow oils. Data for F1-trans: ¹H NMR S (500 MHz, CDCl₃): 8.44 (m, 1H), 7.56 (td, J=7.6, 1.7 Hz, 1H), 7.22 (dd, J=7.8, 1.0 Hz, 1H), 7.08 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 2.58 (ddd, J=10.0, 6.1, 3.9 Hz, 1H), 2.25 (ddd, J=9.5, 5.6, 3.9 Hz, 1H), 1.61, (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LRMS (ES) calculated M+H for C₁₁H₁₃NO₂S: 192.2. Found: 192.1. Enantiomers were resolved by chiral preparative SFC (3.0 cm i.d.×25 cm ChiralTech IC, 7% EtOH/CO₂, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d.×25 cm ChiralTech IC, 7% EtOH/CO₂, 2.4 mL/min) ent₁=3.6 min, ent₂=4.1 min. Using this method, the (S,S) enantiomer was determined to the first eluting peak and was isolated in >99% ee.

(S,S)-2-(Pyridin-2-yl)cyclopropylimethanol (F2)

A solution of (S,S)-F1-trans (751 mg, 3.93 mmol) in THF (20 mL) was cooled to 0° C. and treated slowly with lithium aluminum hydride (3.93 mL, 3.93 mmol, 1 M solution in THF). The solution was warmed to room temperature and stirred for 20 min. The reaction mixture was then re-cooled to 0° C. and treated sequentially dropwise with 0.15 mL of water, 0.15 ml of 15% NaOH, and 0.45 mL of water. Sodium sulfate was added to the mixture. After stirring at room temperature for 10 min, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil. The material was sufficiently pure to use in the subsequent step without further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.41 (d, J=4.2 Hz, 1H), 7.52 (td, J=7.6, 1.7 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.03 (ddd, J=7.3, 4.9, 0.7 Hz, 1H), 3.72 (dd, J=11.2, 6.4 Hz, 1H), 3.57 (dd, J=11.2, 7.1 Hz, 1H), 2.26 (bs, 1H), 1.98 (m, 1H), 1.74 (m, 1H), 1.25 (m, 1H), 0.96 (m, 1H) ppm; LRMS (ES) calculated M+H for C₉H₁₁NO: 150.2. Found: 150.1. As an alternate means to resolving enantiomers of this building block, enantiomers of racemic F2 could be resolved by chiral preparative SFC (3.0 cm i.d.×25 cm ChiralPak AD-H, 3:7:90 MeCN/MeOH/CO₂, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d.×25 cm ChiralPak AD-H, 3:7:90 MeCN/MeOH/CO₂, 2.4 mL/min) ent₁=7.5 min, ent₂=8.4 min. Using this method, the (S,S) enantiomer was determined to be the second eluting peak and was isolated in 98.7% ee.

Example 2

2-Vinylquinoline (G1)

A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh₃)₄ (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). All spectral data matched literature values. Fakhfakh, M. A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2001, 42, 3847. LRMS m/z (M+H) 156.1 found, 156.2 required.

Ethyl 2-(quinolin-2-yl)cyclopropanecarboxylate (G2-trans)

A solution of G1 (941 mg, 6.06 mmol) in toluene (20 ml) was treated with ethyl diazoacetate (0.629 mL, 6.06 mmol) and stirred at reflux overnight. The mixture was concentrated and the residue was purified directly by gradient elution on silica gel (0 to 30% EtOAc in hexanes) to elute peak 1 (trans diastereomer). The eluent was then ramped up (50% EtOAc in hexanes) to elute peak 2 (cis diastereomer). This afforded the title compound as a pale yellow oil (706 mg, 40%, ca. 70% pure), which could be used in the subsequent step without further purification. LRMS m/z (M+H) 242.2 found, 242.3 required.

(S,S)-2-(Quinolin-2-yl)cyclopropyl]methanol (G3)

A solution of the G2-trans (200 mg, 0.829 mmol) in THF (20 mL) was cooled to 0° C. and treated slowly with a 1M THF solution of LiAlH₄ (0.829 mL, 0.829 mmol). The solution was warmed to room temperature and stirred for 20 min. The mixture was re-cooled to 0° C. and treated dropwise with 0.03 mL of water, 0.03 ml of 15% NaOH, and 0.09 mL of water successively. Sodium sulfate was added to the mixture, and after stirring at room temperature for 10 min, the mixture was filtered through Celite, eluting exhaustively with CH₂Cl₂ and MeOH. The filtrate was concentrated in vacuo, and the resulting residue was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes) to afford the title compound as a colorless oil (130 mg, 79%). ¹H NMR (500 MHz, CDCl₃): δ 7.93 (d, J=3.5 Hz, 1H), 7.90 (d, J=3.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.59 (td, J=7.6, 1.4 Hz, 1H), 7.38 (td, J=7.6, 1.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 3.76 (dd, J=11.4, 6.0 Hz, 1H), 3.56 (dd, J=11.4, 7.2 Hz, 1H), 2.15 (dt, J=8.5, 4.4 Hz, 1H), 1.84 (m, 1H), 1.33 (dt, J=8.6, 4.4 Hz, 1H), 1.01 (ddd, 0.5=10.4, 5.9, 1.1 Hz, 1H) ppm; LRMS m/z (M+H) 200.1 found, 200.2 required. Enantiomers were resolved by chiral preparative SFC (3.0 cm i.d.×25 cm ChiralPak AD-H, 30% MeOH/CO₂+0.1% DEA, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d.×25 cm ChiralPak AD-H, 30% MeOH/CO₂+0.1% DEA, 2.4 mL/min) ent₁=2.8 min, ent₂=3.5 min. Using this method, the (S,S) enantiomer was determined to be the first eluting peak and was isolated in >99% ee.

Example 3

Ethyl 3-(1,5-naphthyridin-2-yl)prop-2-enoate (H1)

2-chloro-1,5-naphthyridine (101 mg, 0.614 mmol), boronate ester B1 (195 mg, 0.920 mmol), S-Phos (25.2 mg, 0.061 mmol), K₃PO₄ (391 mg, 1.841 mmol) and PdOAc₂ (6.89 mg, 0.031 mmol) were combined in a 5-mL microwave vial in THF (2.5 mL) and water (500 μl). The reaction mixture was heated at 100° C. for 15 min. The reaction mixture was diluted with EtOAc (20 mL), washed with sat. aq. NaHCO₃ (25 mL) and brine (25 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (10 to 100% EtOAc in hexanes) to afford the title compound as a pale orange solid (118 mg, 90%). ¹H NMR (500 MHz, DMSO): δ 9.02 (dd, J=4.1, 1.6 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.48-8.42 (m, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.84-7.79 (m, 2H), 7.13 (d, J=16.0 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H) ppm; LRMS m/z (M+H) 229.2 found, 229.1 required.

Ethyl 2-(1,5-naphthyridin-2-yl)cyclopropanecarboxylate (H2)

To a 5-mL sealed vial was added trimethyl sulfoxonium iodide (170 mg, 0.770 mmol), DMSO (2567 μl), and NaH (26.7 mg, 0.668 mmol). This mixture was stirred for 40 min at 50° C. The reaction mixture was then cooled to room temperature and to it was added a solution of H1 (110 mg, 0.513 mmol) in DMSO (1.5 mL). The reaction mixture was stirred at room temperature for 5 min, and then diluted with EtOAc (75 mL) and washed with sat. aq. NaHCO₃ (4×20 mL). The organics were dried over MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (20 to 100% EtOAc in hexanes) to afford the title compound (67 mg, 57%). ¹H NMR (500 MHz, CDCl₃): δ 8.89 (dd, J=4.2, 1.6 Hz, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.60-7.57 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.82-2.77 (m, 1H), 2.47-2.42 (m, 1H), 1.79 (ddd, J=8.6, 6.0, 3.8 Hz, 1H), 1.71 (ddd, J=8.9, 5.6, 3.8 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H) ppm; LRMS m/z (M+H) 243.3. Found, 243.3 required.

(S,S)-[2-(1,5-Naphthyridin-2-yl)cyclopropyl]methanol (H3)

The title compound was prepared on a 1.1-gram (3.86 mmol) scale from 82 according to the protocol outlined in Example 1, to afford the title compound as a brown gum (750 mg, 97%). ¹H NMR (500 MHz, CDCl₃): δ 8.86 (dd, J=4.2, 1.6 Hz, 1H), 8.21-8.26 (m, 2H), 7.57 (dd, J=8.5, 4.2 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 3.77 (dd, J=11.3, 6.3 Hz, 1H), 3.68 (dd, J=11.3, 6.9 Hz, 1H), 2.21 (dt, J=8.6, 4.5 Hz, 1H), 1.99-1.92 (m, 1H), 1.48-1.42 (m, 1H), 1.16-1.10 (m, 1H); LRMS m/z (M+H) 201.3 found, 201.2 required. Enantiomers were resolved by chiral preparative SFC (3.0 cm i.d.×25 cm ChiralPak AD-H, 30% MeOH/CO₂+0.1% DEA, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d.×25 cm ChiralPak AD-H, 30% MeOH/CO₂+0.1% DEA, 2.4 mL/min) ent₁=3.4 min, ent₂=4.7 min. Using this method, the (S,S) enantiomer was determined to be the second eluting peak and was isolated in >99% ee.

Example 4

Ethyl 3-(5-methoxypyridin-2-yl)prop-2-enoate (I1)

To a 25-mL microwave vial was added 2-bromo-5-methoxy pyridine (1.88 g, 10 mmol), ethyl acrylate (5.44 ml, 50.0 mmol), Pd(OAc)₂ (0.225 g, 1.000 mmol), K₂CO₃ (4.15 g, 30.0 mmol), and t-butylammonium chloride hydrate (2.96 g, 10.00 mmol). The slurry was heated in the microwave at 160° C. for 1 h. Upon cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and washed with sat. aq. NaHCO3 (100 mL). The aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were then washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to afford the title compound (1.5 g, 72%). ¹H NMR (500 MHz, CDCl₃): δ 8.35 (d, J=3.0 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.18 (dd, J=8.6, 3.0 Hz, 1H), 6.76 (d, J=15.7 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 1.33 (t, J=7.1 Hz, 3H) ppm; LRMS m/z (M+H) 208.0 found, 208.2 required.

Ethyl 2-(5-methoxypyridin-2-yl)cyclopropanecarboxylate (I2)

The title compound was prepared on a 1-gram (4.83 mmol) scale according to the protocol outlined in Example 2 for compound H2. The product was obtained as a light yellow solid (500 mg, 47%). %). NMR (500 MHz, CDCl₃): δ 8.15 (d, J=2.9 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.0, 2.9 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.58-2.52 (m, 1H), 2.18-2.12 (m, 1H), 1.56 (m, 1H), 1.54 (m, 1H), 1.27 (t, J=7.1 Hz, 3H) ppm; LRMS m/z (M+H) 222.3 found, 222.3 required.

(S,S)-[2-(5-Methoxypyridin-2-yl)cyclopropyl]methanol (I3)

The title compound was prepared on a 0.36-gram (1.63 mmol) scale from 12 according to the protocol outlined in Example 1, to afford the title compound as a light yellow oil (290 mg, 99%). ¹H NMR (500 MHz, CDCl₃): δ 8.14 (d, J=2.9 Hz, 1H), 7.09 (dd, J=8.6, 2.9 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 332-3.66 (m, 1H), 3.61-3.55 (m, 1H), 1.97-1.91 (m, 1H), 1.69-1.62 (m, 1H), 1.20-1.14 (m, 1H), 0.91 (1H, dt, J=8.71, 5.06 Hz) ppm; LRMS m/z (M+H) 180.1 found, 180.1 required. Enantiomers were resolved by chiral preparative SFC (3.0 cm i.d.×25 cm ChiralPak AD-H, 6.7/13.3/80 MeCN/MeOH/CO₂, +0.1% DEA, 70 mL/min) and analyzed by chiral analytical SEC (4.6 cm i.d.×25 cm ChiralPak AD-H, 6.7/13.3/80 MeCN/MeOH/CO₂, +0.1% DEA, mL/m) ent₁=3.7 min, ent₂=4.4 min. Using this method, the (S,S) enantiomer was determined to be the second eluting peak and was isolated in >99% ee.

Example 5A

Pyrazolo[1,5-a]pyrimidine-5,7-diol (J1)

Intermediates J1 and J2 were prepared essentially according to the procedure described in US Patent Publication No.: US 2006/0041131 A1. Sodium metal (6.64 g, 289 mmol) was added to EtOH (450 mL) and stirred for 40 min until all was dissolved. Next, ethyl acrylate (24.12 ml, 159 mmol) and 3-aminopyrazole (12.00 g, 144 mmol) were added, and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, filtered, and the collected solids rinsed with excess EtOH. The isolated solids were dissolved in water (˜300 mL), which was cooled with and ice water bath. The aqueous mixture was acidified to pH=1-2 with concentrated HCl. The resulting precipitate was filtered and rinsed with excess water. The isolated solid was dried in a vacuum oven at 30° C. over the weekend to afford the title compound (J1) as an off-white solid (13.5 g, 62%). LRMS m/z (M+H+H₂O) 170.1 found, 152.0 required.

5,7-Dichloropyrazolo[1,5-a]pyrimidine (J2)

POCl₃ (10 mL, 109 mmol) was added to a mixture of J1 (800 mg, 5.29 mmol) and dimethyl aniline (1.8 g, 14.82 mmol) in an ice-cooled round-bottom flask. The reaction mixture was stirred at room temperature for 10 min and then heated to 60° C. for 3 h. The excess POCl₃ was removed in vacuo, and the resulting residue was poured onto ice water. The aqueous solution was basified to pH=9 with solid NaHCO₃. The mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (20 to 80% EtOAc in heptane) to afford the title compound as a white solid (810 mg, 81%). ¹H NMR (300 MHz, CDCl₃): δ 8.22 (d, J=3.0 Hz, 1H), 7.00 (s, 1H), 6.76 (d, J=3.0 Hz, 1H) ppm; LRMS m/z (M+H) 188.1 found, 188.0 required.

5-chloro-N-[(1-Methyl-1H-pyrazol-3-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (J4)

5,7-Dichloropyrazolo[1,5-a]pyrimidine J2 (200 mg, 1.064 mmol), J3 (118 mg, 1.064 mmol), and potassium carbonate (294 mg, 2.127 mmol) were combined in DMF (5.3 mL) and heated to 90° C. for 3 h. The reaction mixture was cooled to room temperature, and diluted with 50 mL EtOAc. The organics were washed with sat. aq. NaHCO₃ (50 mL) and brine (50 mL), dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound as an off-white solid. The resulting product was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 263.3 found, 263.1 required.

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5)

5-Chloro-N-[(1-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine J4 (667 mg, 2.54 mmol), (S,S)-2-(pyridin-2-yl)cyclopropyl]methanol (F2) (398 mg, 2.67 mmol), ligand D6 (282 mg, 0.508 mmol), Pd₂(dba)₃ (233 mg, 0.254 mmol), and Cs₂CO₃ (2.48 g, 7.62 mmol) were combined in toluene (10 mL) in a microwave vial, and heated in a microwave reactor at 140° C. for 20 min. The resulting reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The organics were dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified three times, first by gradient elution on silica gel (0 to 50% [10% MeOH in DCM] in DCM), next by gradient elution on silica gel (0 to 100% [10% MeOH in EtOAc] in hexanes, and finally by gradient elution on reverse phase HPLC (5 to 95% MeCN in water (0.1% TFA)). The pure material was free-based with sat. aq. NaHCO₃ to afford the title compound as a white foam (500 mg, 52.4%). ¹H NMR (500 MHz, CDCl₃): δ 8.45 (d, J=4.9 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.53 (td, J=7.8, 2.0 Hz, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.16 (dd, J=7.8, 1.0 Hz, 1H), 7.05 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 6.29 (bt, J=5.3 Hz, 1H), 6.23 (d, J=2.2 Hz, 1H), 5.49 (s, 1H), 4.41 (dd, J=11.2, 6.6 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H), 4.34 (dd, J=11.2, 7.3 Hz, 1H), 3.90 (s, 3H), 2.11 (dt, J=8.6, 4.9 Hz, 1H), 1.97 (m, 1H), 1.36 (dt, J=8.8, 4.9 Hz, 1H), 1.11 (ddd, J=10.0, 5.6, 4.4 Hz, 1H) ppm; HRMS (ES) calculated M+H for C20H21N7O: 376.1880. Found: 376.1882.

Example 5B

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxyl}pyrazolo[1,5-a]pyrimidin-7-amine (J5)

5,7-Dichloropyrazolo[1,5-a]pyrimidine (J2) (54.0 g, 287 mmol), (J3) (32.5 g, 293 mmol), and Cs₂CO₃ (229 g, 704 mmol) were combined in toluene (938 ml) and heated at 80° C. for 2 h to give the desired product 5-chloro-N-[(1-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (J4). To the suspension of J4 was added a mixture of (S,S)-2-(pyridin-2-yl)cyclopropyl]methanol (F2) (42 g, 282 mmol), ligand D6 (3.12 g, 5.63 mmol), allyl palladium (II) chloride dimer (1.030 g, 2.82 mmol). The resultant mixture was heated at reflux (132° C.) for 2 h. The reaction mixture was cooled to room temperature, filtered through celite, and rinsed with EtOAc (300 mL). The solution was washed with 0.01 N HCl (400 mL×3) to remove unreacted alcohol starting material F2. The organic solution was extracted with 1N HCl (300 mL and then 150 mL). The combined aqueous phase was washed with MTBE (150 mL×2). The aqueous solution was added to 400 mL DCM, cooled to 0-5° C. with ice water, then added 250 mL 2N NaOH slowly with vigorous stirring. The DCM phase was separated and the aqueous phase was extracted two more time with DCM (200 mL×2). The combined DCM solution was dried over Na₂SO₄ (50 gram). The solution was filtered and the dry DCM solution containing product was stirred with 10 gram silia bond DMT for 20 h. The solution was filtered and concentrated to dryness to afford the title compound (88 g) as a white foam.

The X-ray diffraction pattern of the free base compound exhibits a lack of intense diffraction peaks, which is consistent with the characterization of the material as amorphous. The modulated DSC scan of the dried amorphous free base exhibits a glass transition (inflection point) of 33° C. No endothermic events were observed, consistent with the characterization of the sample as amorphous

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) fumarate

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (88 g, 234 mmol), fumaric acid (27.8 g, 239 mmol), acetonitrile (650 ml) and water (130 ml) was mixed, and the mixture was heated to 50° C. (internal temp) for the solids to dissolve. The mixture was cooled to 35° C. and a seed of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (400 mg) was added, and the suspension was stirred at room temperature overnight. The suspension was filtered and rinsed with ACN/water (40 mL, 4:1), dried under humidified N₂ sweep with vacuum for 2 days to afford the desired product as a white crystalline solid (109 g).

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) fumarate anhydrate (form I)

A mixture of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine and fumaric acid (50 mg, 0.431 mmol) was dissolved in MeOH and heated at 60° C. for 30 min The MeOH was removed and the resultant foam solid was redissolved in 2 mL ACN and 0.4 mL MeOH with heating. A seed of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine was added to form a suspension, which was stirred at room temperature overnight. The resultant solid was collected by filtration and rinsed with 1 mL ACN and dried under vacuum to give a white solid.

The X-ray diffraction pattern of the anhydrous fumarate (form 1) exhibits intense diffraction peaks, which is consistent with characterization as a crystalline form. The fumarate is characterized by diffraction peaks corresponding to d-spacings of 9.55, 6.18, 5.35, 3.67, and 3.34 angstroms.

Peak Position, d-Spacing and Peak Height for the anhydrous fumarate (form I)

Pos. [°2-Th.] d-spacing [Å] Height [cps] 9.3 9.55 25.8 14.3 6.18 98.9 16.6 5.35 151.1 24.3 3.67 199.2 26.6 3.35 110.9

The DSC scan of the anhydrous fumarate (form I) is characterized by an onset temperature of 134° C. and a peak temperature of 138° C. The associated heat of fusion is not reported due to decomposition simultaneous with the melt.

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) fumarate anhydrate (form II)

A mixture of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.133 mmol) and fumaric acid (16 mg, 0.138 mmol) in IPA was heated until the solids dissolved and then cool to room temperature and aged overnight. The resultant solid was collected by filtration and dried.

The X-ray diffraction pattern of the anhydrous fumarate (form II) exhibits intense diffraction peaks, which is consistent with characterization as a crystalline form. The fumarate II is characterized by diffraction peaks corresponding to d-spacings of 8.31, 5.73, 4.55, 3.79, and 3.39 angstroms.

Peak Position, d-Spacing and Peak Height for the anhydrous fumarate (form II)

Pos. [°2-Th.] d-spacing [Å] Height [cps] 10.6 8.31 476.4 15.5 5.73 679.6 19.5 4.55 438.7 23.5 3.79 390.7 26.3 3.39 307.0

The DSC scan of the anhydrous fumarate (form II) is characterized by an onset temperature of 119° C. and a peak temperature of 122° C. The associated heat of fusion is not reported due to decomposition simultaneous with the melt.

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) fumarate sesquihydrate (form III)

To a mixture of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (1000 mg, 2.66 mmol) and fumaric acid (320 mg, 2.76 mmol) was added MeCN (10 mL) and H₂O (1 mL). The mixture was heated until the solids dissolved, then cooled, a seed of (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine was added and the mixture was stirred overnight. The resultant solid was collected by filtration and rinsed with 5 mL ACN and dried under vacuum at 40° C. for 4 h.

The X-ray diffraction pattern of the 1.5 hydrated fumarate (form III) exhibits intense diffraction peaks, which is consistent with characterization as a crystalline form. The hydrated fumarate III is characterized by diffraction peaks corresponding to d-spacings of 12.01, 6.48, and 5.71 angstroms.

Peak Position, d-Spacing and Peak Height for the 1.5 hydrated fumarate (fowl III).

Pos. [°2-Th.] d-spacing [Å] Height [cps] 7.4 12.01 332.2 13.6 6.48 207.0 15.5 5.71 526.9

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) fumarate trihydrate (form IV)

To (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine fumarate sesquihydrate (6.401 mg) was added 10% Tween 80 (88 uL) and the mixture was stirred overnight. The resultant solid was isolated by filtration.

The X-ray diffraction pattern of the trihydrated fumarate (form IV) exhibits intense diffraction peaks, which is consistent with characterization as a crystalline form. The hydrated fumarate IV is characterized by diffraction peaks corresponding to d-spacings of 12.55, 11.05, 6.69, 4.92, and 4.17 angstroms.

Peak Position, d-Spacing and Peak Height for the trihydrated hydrated fumarate (form IV)

Pos. [°2-Th.] d-spacing [Å] Height [cps] 7.0 12.55 351.5 8.0 11.05 590.6 13.2 6.69 377.0 18.0 4.92 194.1 21.3 4.17 617.2

(S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (J5) hydrochloride

To a mixture of (S,S)—N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine fumarate in water (500 mL) and DCM (300 mL) was added NaHCO₃ (16.45 g, 196 mmol) in four portions with vigorous stirring. The mixture was stirred for 30 min. The two phase solution was separated and the aqueous phase was extracted one time with DCM (200 mL). The combined DCM layer was dried and concentrated to dryness to give the free base as an off white foam. The free base was dissolved in 2-Propanol (650 ml) and the solution was warmed to 40° C. To the solution was added HCl 4M in dioxane (40.8 ml, 163 mmol) slowly via syringe. Isopropyl acetate was added to the resulting solution. An aliquat was removed to a vial, and was scratched to form crystals. The batch was seeded with the crystals from the vial and aged at 40° C. 1 h. Heating was discontinued, the mixture was allowed to cool to room temperature and aged at room temperature overnight. The solids were collected by vacuum filtration and washed w/isopropyl acetate. The collected solid was dried on the filter under nitrogen overnight, to afford the desired product as a pale yellow solid (59.1 g).

The X-ray diffraction pattern of the hydrochloride salt exhibits intense diffraction peaks, which is consistent with characterization as a crystalline salt. The hydrochloride is characterized by diffraction peaks corresponding to d-spacings of 15.96, 8.72, 5.26, 3.65, and 3.36 angstroms.

Peak Position d-Spacing and Peak Height for the Hydrochloride Salt

Pos. [°2-Th.] d-spacing [Å] Height [cps] 5.5 15.96 197.7 10.1 8.72 135.8 16.9 5.26 246.4 24.4 3.65 256.9 26.5 3.36 193.6

The DSC scan of the hydrochloride salt is characterized by an onset temperature of 164.1° C. and a peak temperature of 165.5° C. The associated heat of fusion is not reported due to decomposition simultaneous with the melt.

Example 6

N-[(1-Benzyl-1H-pyrazol-3-yl)methyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-amine (L2)

A suspension of J2 (88 mg, 0.47 mmol), L1 (88 mg, 0.47 mmol), and potassium carbonate (129 mg, 0.94 mmol) in DMF (2.0 mL) was heated to 90° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed sequentially with sat. aq. NaHCO₃ (20 mL) and brine (20 mL). The organics were dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a light yellow solid. The unpurified material was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 339.3 found, 339.1 required.

(S,S)—N-[(1-Benzyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine (L3)

The title compound was prepared on a 0.25-gram (0.738 mmol) scale from L2 and F2 according to the protocol outlined in Example 5, to afford the title compound as a colorless gum (225 mg, 64%). ¹H NMR (500 MHz, CDCl₃): δ 8.44 (d, J=4.2 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.55 (s, 1H), 7.53 (dt, J=7.8, 1.7 Hz, 1H), 7.40 (s, 1H), 7.25-7.40 (m, 3H), 7.20-7.24 (m, 2H), 7.14 (d, J=7.8 Hz, 1H), 7.04 (dd, J=6.6, 5.9 Hz, 1H), 6.24 (bt, J=5.1 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 5.47 (s, 1H), 5.28 (s, 2H), 4.27-4.46 (m, 4H), 2.05-2.15 (m, 1H), 1.91-1.98 (m, 1H), 1.30-1.41 (m, 1H), 1.05-1.12 (m, 1H) ppm; HRMS (ES) calculated M H for C25H25N7: 452.2193. Found: 452.2193.

(S,S)—N-(1H-Pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine (L4)

L3 (22 mg, 0.049 mmol) and DMSO (34.6 μl, 0.487 mmol) were combined in a 10-mL round-bottom flask. With stirring at room temperature, a 1M THF solution of KOt-Bu (341 μl, 0.341 mmol) was added dropwise. Next, O₂ was bubbled through the reaction mixture through a Pasteur pipette for 10 min, replenishing the level of THF at ca. 2-minute intervals as the solvent was evaporated. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with sat. aq. NaHCO₃ (10 mL) and brine (10 mL). The combined organics were dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by preparative thin layer chromatography (5% MeOH/EtOAc) to afford the title compound as a colorless gum (13 mg, 74%). NMR (500 MHz, CDCl₃): δ 8.44 (d, J=4.2 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.60 (m, 2H), 7.53 (dt, J=7.8, 2.0 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.05 (ddd, J=7.6, 4.9, 1.0 Hz, 1H), 6.41 (bt, J=5.2 Hz, 1H), 6.22 (d, J=2.2 Hz, 1H), 5.49 (s, 1H), 4.35-4.43 (m, 3H), 4.33 (dd, J=11.0, 7.3 Hz, 1H), 2.06-2.14 (m, 1H), 1.92-1.97 (m, 1H), 1.29-1.39 (m, 1H), 1.07-1.12 (m, 11-1) ppm; HRMS (ES) calculated M H for C25H25N7: 362.1720. Found: 362.1724.

Example 7

5-Chloro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (M2)

J2 (600 mg, 3.19 mmol) and M1 (897 mg, 4.79 mmol) were combined with TEA (1.56 mL, 11.17 mmol) in toluene (10 mL). The reaction mixture was heated to 70° C. overnight, and then allowed to stand at room temperature for 5 days. At this time, product had precipitated out of the reraction mixture. Water (20 mL) was added, and the suspension filtered under vacuum. The collected solid was washed with excess Et₂O, and dried to afford the title compound as a light yellow solid which was sufficiently pure to use in the subsequent step without further purification (842 mg, 94%). LRMS m/z (M+H) 281.1 found, 281.0 required.

5-{[(1R,2R)-2-(6-Methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (M3)

M2 (5.23 g, 18.61 mmol), 113 (2.78 g, 15.51 mmol), Cs₂CO₃ (8.84 g, 27.1 mmol), D6 (1.72 g, 3.10 mmol), and Pd₂dba₃ (1.42 g, 1.55 mmol) were combined in a 350-mL pressure vessel in toluene (60 mL). The stirring mixture was degassed under a stream of N₂ for 5 min at room temperature. Next, the vessel was sealed tightly and heated to 140° C. for 1 h. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (250 mL) and brine (250 mL). The organics were dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 50% [10% MeOH in CH₂Cl₂] in CH₂Cl₂), then by gradient elution on silica gel (0 to 80% [10% MeOH in EtOAc] in hexanes), and then by preparative reverse phase chromatography (15 to 80% CH₃CN in water (0.1% TFA)). The free-based product was dissolved in CH₂Cl₂ (100 mL) and treated with SiliaBond DMT (1 g, 40-63 μm, 0.57 mmol/g) and stirred at room temperature for 4 h. The mixture was filtered through a scintered glass funnel and the filtrate was concentrated to provide the title compound as a bright white solid (3.15 g, 48%). ¹H NMR (500 MHz, CDCl₃): δ 8.17 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.00-7.17 (m, 2H), 6.84 (bt, J=5.4 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 5.56 (s, 1H), 4.94 (d, J=6.4 Hz, 2H), 4.39 (dd, J=11.1, 6.6 Hz, 1H), 4.30 (dd, J=11.1, 7.3 Hz, 1H), 3.83 (s, 3H), 2.77 (s, 3H), 2.50-2.10 (m, 1H), 1.80-1.89 (m, 1H), 1.27 (td, J=8.5, 4.9 Hz, 1H), 1.03 (td, J=8.8, 5.1 Hz, 1H) ppm; HRMS (ES) calculated M+H for C20H21N7O2S: 424.1550. Found: 424.1557.

Example 8

trans 2-[2-(bromomethyl)cyclopropyl]quinoline (N1)

A solution of G3 (117 mg, 0.587 mmol) in CH₂Cl₂ (10 ml) was treated dropwise with thionyl bromide (0.137 ml, 1.762 mmol). The solution was stirred at room temperature for 1.5 hr. The mixture was concentrated in vacuo and the residue was partitioned between sat. aq. NaHCO₃ (10 mL) and EtOAc (10 mL). The organic phase was washed with sat. aq. NaHCO₃ (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to afford the title compounds as a colorless oil (96.7 mg, 63%). ¹H NMR (500 MHz, CDCl₃): δ 8.01 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 3.60 (dd, J=10.3, 7.3 Hz, 1H), 3.48 (dd, J=10.3, 7.8 Hz, 1H), 2.26 (dt, J=8.8, 4.9 Hz, 1H), 2.13 (m, 1H), 1.72 (dt, J=8.5, 4.9 Hz, 1H), 1.17 (dt, J=8.8, 5.4 Hz, 1H) ppm; LRMS m/z (M+H) 264.2 found, 264.0 required.

ethyl 3-oxo-5-[2-(quinolin-2-yl)cyclopropyl]pentanoate (N2)

To a 0° C. stirred suspension of NaH (54.9 mg, 1.373 mmol) in THF (3 mL) was added dropwise methyl acetoacetate (0.074 ml, 0.687 mmol). After being stirred at 0° C. for 10 min and at room temperature for 1 hr, a 1.6 M hexanes solution of n-BuLi (0.412 ml, 1.030 mmol) was added dropwise and the yellow to orange dianion solution was stirred for an additional 10 min. Next, N1 (90 mg, 0.343 mmol) was added as a solution in THF (0.2 mL). The reaction mixture was stirred overnight at room temperature and was then diluted with EtOAc (15 mL) and washed with sat. aq. NaHCO₃ (15 mL) and brine (15 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to afford the title compound as a colorless oil (28 mg, 27%). ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J=8.5 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.59 (td, J=7.7, 1.5 Hz, 1H), 7.38 (td, J=7.6, 1.2 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 3.66 (s, 3H), 3.42 (s, 2H), 2.68 (t, J=7.3, 2H), 1.97 (dt, J=8.4, 4.4 Hz, 1H), 1.62-1.85 (m, 2H), 1.51 (m, 1H), 1.30-1.41 (m, 1H), 0.85-0.95 (m, 1H) ppm; LRMS m/z (M+H) 298.3 found, 298.3 required.

5-{2-[-2-(quinolin-2-yl)cyclopropyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-ol (N3)

N2 (28 mg, 0.094 mmol) and 1-aminopyrazole (7.82 mg, 0.094 mmol) were combined in a 2-dram vial. The reagents were diluted with AcOH (200 μl) and heated with stirring to 90° C. for 2 h. The mixture was concentrated to dryness and purified by isocratic elution on a preparative TLC plate (10% MeOH in DCM). The desired band was isolated, washed with 10 mL 10:1 DCM:MeOH and filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless film (17 mg, 55%). LRMS m/z (M+H) 331.4 found, 331.4 required.

2-{-2-[2-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethyl]cyclopropyl}quinoline (N4)

N3 (17 mg, 0.05 mmol) was treated with POCl₃ (4.85 μl, 0.052 mmol) and the resulting reaction mixture was heated to 85° C. for 20 min. The mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with EtOAc (5 mL) and washed with sat. aq. NaHCO₃ (5 mL). The organic phase was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a yellow film. The resulting product was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 349.3 found, 349.1 required.

N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{2-[2-(quinolin-2-yl)cyclopropyl]ethyl}-pyrazolo[1,5-a]pyrimidin-7-amine (N5)

N4 (25 mg, 0.072 mmol), J3 (15.93 mg, 0.143 mmol), and potassium carbonate 34.7 mg, 0.251 mmol) were combined in DMF (0.5 mL), sealed in a 1-dram vial, and stirred at 90° C. for 30 min. The reaction mixture was diluted with EtOAc (5 mL) and washed with sat. aq. NaHCO₃ (5 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by isocratic elution on a preparative TLC plate (5% MeOH in DCM). The desired band was isolated, washed with 10 mL 10:1 DCM:MeOH and filtered. The filtrate was concentrated in vacuo to afford the title compound as a tan gum (18.8 mg, 61.9%). ¹H NMR (500 MHz, CDCl₃): δ 7.70-7.95 (m, 3H), 7.72 (d, J=8.1, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.43 (t, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.41 (d, J=2.2 Hz, 1H), 6.22 (bt, J=4.9 Hz, 1H), 5.79 (s, 1H), 4.12 (dd, J=14.3, 5.1 Hz, 1H), 4.05 (dd, J=14.3, 5.4 Hz, 1H), 3.87 (s, 3H), 2.86-2.97 (m, 2H), 2.00-2.15 (m, 1H), 1.95 (dt, J=8.3, 4.4 Hz, 1H), 1.80-1.90 (m, 1H), 1.57 (m, 1H), 1.39 (dt, J=8.5, 4.6 Hz, 1H), 0.99 (dt, J=8.3, 5.4 Hz, 1H) ppm; HRMS (ES) calculated M+H for C25H25N7: 424.2243. Found: 424.2244.

Example 9

ethyl 7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxylate (O1)

To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylate (2.0 g, 8.9 mmol) in 15 mL DMSO were added (1-methyl-1H-pyrazol-4-yl)methanamine and triethylamine (2.69 g, 3.71 mL, 26.6 mmol), and the mixture was heated at 100° C. under microwave irradiation for 15 minutes. The reaction was then added to water (50 mL), and the precipitate was collected by filtration. The resulting white solid was carried forward without further purification. MS (Electrospray): m/z 301.2 (MH⁺).

7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (O2)

To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylate O1 (150 mg, 0.50 mmol) in 2.5 mL THF was added 1 M aq. LiOH (0.50 mL), and the mixture was allowed to stir for 16 h. All volatiles were removed under vacuum to give a white solid that was carried forward without further purification. MS (Electrospray): m/z 273.1 (MH⁺).

N-(2-(1,5-naphthyridin-2-yl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxamide (O3)

7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid O2 (263 mg, 0.97 mmol) and 2-(1,5-naphthyridin-2-yl)ethanamine (167 mg, 0.97 mmol) were dissolved in 5 mL DMF. Triethylamine (98 mg, 135 EL, 0.97 mmol) and (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) (TBTU) (310 mg, 0.97 mmol) were then added. After stirring for 1 hour, the mixture was concentrated under vacuum and purified by reverse phase chromatography to give 26.4 mg (6.4%) of O3 as an off-white solid. ¹H NMR δ (ppm) (DMSO-d₆): 9.04 (1H, d, J=6.44 Hz), 8.97 (1H, d, J=4.13 Hz), 8.67 (1H, d, J=6.93 Hz), 8.39 (2H, dd, J=20.18, 8.59 Hz), 8.20 (1H, d, J=2.32 Hz), 7.79 (1H, dd, J=8.50, 4.23 Hz), 7.74 (1H, d, J=8.69 Hz), 7.63 (1H, s), 7.40 (1H, s), 6.73 (1H, s), 6.54 (1H, d, J=2.33 Hz), 4.51 (2H, d, J=6.29 Hz), 3.76 (3H, s), 2.99 (1H, s). HRMS (ES) calculated M+H for C₂₃H₂₄ClN₅OS: 428.1942. Found: 428.1946.

TABLE 1 The following compounds were prepared using the foregoing methodology, but substituting the appropriately substituted reagent, as described in the foregoing Reaction Schemes and Examples. Cpd. Structure Name HRMS m/z (M + H) 1-1 

5-{[2-(5- fluoropyridin-2- yl)cyclopropyl] methoxy}-N-[(1- methyl-1H-pyrazol- 4-yl)methyl]pyrazolo [1,5-a]pyrimidin-7- amine 394.1788 found, 394.1786 required. 1-2 

N-{2-[(5-{[2- (quinolin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5- a]-pyrimidin-7- yl)amino]- ethyl}acetamide 417.2029 found, 417.2034 required. 1-3 

N-[(2,4-dimethyl- 1,3-oxazol-5- yl)methyl]-5-{[2-(5- methoxy-pyridin-2- yl)cyclopropyl]- methoxy}pyrazolo [1,5-a]pyrimidin-7- amine 421.1979 found, 421.1983 required. 1-4 

(S,S)-N-[(2-methyl- 1,3-thiazol-5- yl)-methyl]-5-{[2- (pyridin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5- a]pyrimidin-7- amine 393.1485 found, 393.1492 required. 1-5 

5-{[2-(quinolin-2- yl)cyclopropyl] methoxy}-N-(1,3- thiazol-5- ylmethyl)pyrazolo [1,5-a]pyrimidin-7- amine 429.1487 found, 429.1492 required. 1-6 

(S,S)-5-{[2-(pyridin- 2-yl)cyclopropyl] methoxy}-N- (pyridin-3- ylmethyl)pyrazolo [1,5-a]pyrimidin-7- amine 373.1769 found, 373.1771 required. 1-7 

(S,S)-N-[2-(1- methyl-1H-pyrazol- 4-yl)ethyl]-5-{[2- (5-methylpyridin-2- yl)cyclo-propyl]- methoxy}pyrazolo [1,5-a]pyrimidin-7- amine 404.2187 found, 404.2193 required. 1-8 

(S,S)-N-[(5-methyl- 1,3,4-thiadiazol-2- yl)methyl]-5-{[2- (pyridin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5-a] pyrimidin-7- amine 394.1434 found, 394.1445 required. 1-9 

5-cyclopropyl-N- [(2,4-dimethyl-1,3- thiazol-5- yl)methyl]pyrazolo [1,5-a]pyrim-idin-7- amine 300.1274 found, 300.1277 required. 1-10

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5-[4-(5- methoxy-pyridin-2- yl)butyl]pyrazolo [1,5-a]pyrimidin-7- amine 423.1966 found, 423.1962 required. 1-11

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5-{2-[2- (5-methoxy-pyridin- 2-yl)cyclo- propyl]ethyl}pyrazolo [1,5-a]pyrimidin- 7-amine 435.1967 found, 435.1962 required. 1-12

2-methyl-1- [(5-{2-[2-(5- methylpyridin-2- yl)cyclopropyl]ethyl} pyrazolo[1,5- a]pyrimidin-7- yl)amino]propan-2-ol 366.2295 found, 366.2288 required. 1-13

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5-{1-[2- (pyridin-2- yl)cyclopropyl] propan-2- yl}pyrazolo[1,5-a] pyrimidin-7- amine 419.2018 found, 419.2012 required. 1-14

N-[(1-methyl-1H- pyrazol-4- yl)methyl]-5-{2-[2- (quinolin-2- yl)cyclopropyl]ethyl} pyrazolo[1,5-a] pyrimidin-7- amine 424.2243 found, 424.2244 required. 1-15

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5-[4- (quinolin-2-yl)but- 3-yn-1- yl]pyrazolo[1,5-a] pyrimidin-7- amine 439.1714 found, 439.1699 required. 1-16

5-[4-(5- methoxypyridin-2- yl)butyl]-N,N- dimethylpyrazolo [1,5-a]pyrimidin-7- amine 326.1981 found, 326.1975 required. 1-17

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5-[4-(5- methoxy-pyridin-2- yl)but-3-yn-1- yl]pyrazolo[1,5-a] pyrimidin-7- amine 419.1659 found, 419.1649 required. 1-18

6-fluoro-N-[(5- methyl-1,3,4- thiadiazol-2- yl)methyl]-5- {[(1S,2S)-2- (pyridin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5-a] pyrimidin-7- amine 412.1357 found, 412.1350 required. 1-19

2-methyl-N-[(1- methyl-1H-pyrazol- 4-yl)methyl]-5- {[(1S,2S)-2- (pyridin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5-a] pyrimidin-7- amine 390.2041 found, 390.2037 required. 1-20

6-methyl-N-[(1- methyl-1H-pyrazol- 4-yl)methyl]-5- {[(1S,2S)-2- (pyridin-2- yl)cyclopropyl] methoxy} pyrazolo[1,5-a] pyrimidin-7- amine 390.2041 found, 390.2037 required. 1-21

N-[(2,4-dimethyl- 1,3-thiazol-5- yl)methyl]-5- (pyridin-3- yl)pyrazolo[1,5-a] pyrimidin-7- amine 337.1235 found, 337.1230 required. 1-22

5-{[(1S,2S)-2-(5- methylpyridin-2- yl)cyclopropyl] methoxy}- 7-[(6-methylpyridin-3- yl)oxy]pyrazolo[1,5-a] pyrimidine 388.1774 found, 388.1768 required. 1-23

7-((2,4- dimethylthiazol-5- yl)methylamino)-N- (((1S,2S)-2- (quinolin-2- yl)cyclopropyl)methyl) pyrazolo[1,5-a] pyrimidine-5- carboxamide 484.1924 found, 484.1914 required. 1-24

7-((1,3-dimethyl- 1H-pyrazo1-5- yl)methylamino)-N- (((1S,2S)-2- (quinolin-2- yl)cyclopropyl)methyl) pyrazolo[1,5-a] pyrimidine-5- carboxamide 467.2302 found, 467.2302 required. 1-25

7-((2,4- dimethylthiazol-5- yl)methylamino)-N- (2-(pyridin-2- yl)ethyl)pyrazolo [1,5-a] pyrimidine-5- earboxanaide 408.1617 found, 408.1601 required. The requisite starting materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis without undue experimentation. Final products were purified by either gradient elution on SiO₂ (EtOAc/hexanes or MeOH/CH₂Cl₂), reverse phase flash chromatography (MeCN/H₂O), or preparative thin layer chromatography (EtOAc/hexanes or MeOH/CH₂Cl₂ or MeOH/EtOAc), and were isolated as free-bases.

TABLE 2 The compounds of the following examples had activity in inhibiting the human PDE10 enzyme in the aforementioned assays with an Ki of about 0.001 nM to about 100 nM: J-5, L-4, M-3, )-3, 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25. The compounds of the following examples had activity in inhibiting the human PDE10 enzyme in the aforementioned assays with an Ki of about 0.001 nM to about 10 nM: J-5, L-4, M-3, 1-3, 1-4, 1-9, 1-10, 1-15, 1-18, 1-20, 1-23, 1-25. The following table shows representative data for the compounds of the Examples as PDE10 inhibitors as determined by the foregoing assays. In this table, the PDE10 Ki is a measure of the ability of the test compound to inhibit the action of the PDE10 enzyme. PDE10A Ki Compound Structure (nM) J-5 

 0.32 L-4 

 0.24 M-3 

 0.012 1-3 

1.3 1-4 

 0.11 1-9 

9.2 1-10

 0.37 1-13

76.9  1-15

 0.14 1-18

 0.08 1-20

 2.52 1-22

20.0  1-23

 0.18 1-25

1.1

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. 

What is claimed is:
 1. A compound of the formula I:

wherein: X is —NR⁴R⁵ or —O—R⁵; Y is —O—, —(CR³R⁴)—, —(C═O)NR⁴—, or a bond between the carbon of the pyrazolopyrimidine ring and R¹; R¹ is C₁₋₆alkyl, C₁₋₆alkyl-C₃₋₆cycloalkyl-, or —CH₂CH₂—C═C— which is unsubstituted or substituted with a substituent selected from the group consisting of (1) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, or C₃₋₆cycloalkyl, (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl, or C₃₋₆cycloalkyl, (3) phenyl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸, (4) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸, (5) —O-phenyl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸, and (6) —O-heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸; R² is selected from the group consisting of: (1) hydrogen, (2) fluoro, (3) C₁₋₆alkyl, and (4) C₃₋₆cycloalkyl; R³ is selected from the group consisting of: (1) hydrogen, and (2) C₁₋₆alkyl; R⁴ is selected from the group consisting of: (1) hydrogen, and (2) C₁₋₆alkyl; R⁵ is C₁₋₆alkyl, C₁₋₆alkyl-C₃₋₆cycloalkyl or C₂₋₆alkenyl which is unsubstituted or substituted with a substituent selected from the group consisting of: (1) halogen, (2) hydroxyl, (3) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen or hydroxyl, (4) phenyl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸, and (5) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R⁶, R⁷ and R⁸; R⁶, R⁷ and R⁸ are independently selected from the group consisting of: (1) halogen, (2) hydroxyl, (3) C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (5) C₃₋₆cycloalkyl, (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen and C₁₋₆alkyl, (7) —(C═O)—NR¹⁰R¹¹, (8) —S(O)₂—NR¹⁰R¹¹, (9) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is selected from the group consisting of hydrogen and C₁₋₆alkyl, and (10) —CN; R¹³ is selected from the group consisting of: (1) hydrogen, and (2) C₁₋₆alkyl; R¹⁴ is selected from the group consisting of: (1) hydrogen, and (2) C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 2 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 2 of the formula Ic:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 2 of the formula Id:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is —CH₂CH₂CH₂— or —CH₂-cyclopropyl-, which is substituted with a substituent selected from the group consisting of: (1) C₁₋₆alkyl, which is unsubstituted or substituted with halogen or hydroxyl, (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen or hydroxyl, (3) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (4) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, (5) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro, and (6) —O-heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), —O—C₁₋₆alkyl or C₁₋₆alkyl, which is unsubstituted or substituted with fluoro.
 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:


8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.
 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from the group consisting of:


10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from the group consisting of:


11. A compound which is selected from the group consisting of: N-[(1-methyl-1,1-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)—N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)—N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[2-(6-methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[(1R,2R)-2-(6-Methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[(1S,2S)-2-(6-Methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine; N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{2-[2-(quinolin-2-yl)cyclopropyl]ethyl}-pyrazolo[1,5-a]pyrimidin-7-amine; N-(2-(1,5-naphthyridin-2-yl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 5-{[2-(5-fluoropyridin-2-yl)cyclopropyl]methoxy)-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazolo pyrimidin-7-amine; N-(2-[(5-[2-(quinolin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]-pyrimidin-7-yl)amino]ethyl acetamide; N-[(2,4-dimethyl-1,3-oxazol-5-yl)methyl]-5-{[2-(5-methoxy-pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)—N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)—N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[2-(quinolin-2-yl)cyclopropyl]methoxy}-N-(1,3-thiazol-5-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)—N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)—N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (S,S)—N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; (R,R)—N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 5-cyclopropyl-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine; N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(5-methoxy-pyridin-2-yl)butyl]pyrazolo[1,5-a]pyrimidin-7-amine; N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-{2-[2-(5-methoxy-pyridin-2-yl)cyclo-propyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 2-methyl-1-[(5-{2-[2-(5-methylpyridin-2-yl)cyclopropyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]propan-2-ol; N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-{1-[2-(pyridin-2-yl)cyclopropyl]propan-2-yl}pyrazolo[1,5-a]pyrimidin-7-amine; N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{2-[2-(quinolin-2-yl)cyclopropyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(quinolin-2-yl)but-3-yn-1-yl]pyrazolo[1,5-a]pyrimidin-7-amine; 5-[4-(5-methoxypyridin-2-yl)butyl]-N,N-dimethylpyrazolo[1,5-a]pyrimidin-7-amine; N-[2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(5-methoxy-pyridin-2-yl)but-3-yn-1-yl]pyrazolo[1,5-a]pyrimidin-7-amine; 6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[(R1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 6-methyl-N-[(1-methyl-1-[1H-pyrazol-4-yl)methyl]-5-{[(1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; 6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine; N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine; 5-{[2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine; 5-{[(1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine; 5-{[(1R,2R)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine; 7-((2,4-dimethylthiazol-5-yl)methylamino)-N-((2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(((1R,2R)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-((2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-(((1R,2R)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(2-(pyridin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; or a pharmaceutically acceptable salt thereof.
 12. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 13. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in medicine.
 14. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders.
 15. A method for treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 16. A method for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 17. A method for treating schizophrenia in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 